We propose to test the approach that shifts the focus from stress response to stress resilience, and the facilita- tion of neuroprotective therapeutic processes that may serve as effective treatment in neurodegenerative dis- orders such as HD. We demonstrated that partial inhibition of mitochondrial complex I activity with small mole- cules developed in our laboratory induces multiple mechanisms of stress resilience that overlap with mecha- nisms of longevity. These small molecules penetrate the blood brain barrier and accumulate in mitochondria where they partially inhibit the activity of mitochondrial complex I. The adaptive response to this mild stress re- sults in the activation of molecular mechanisms that induce a protection against oxidative stress, the en- hancement of cellular energetics, restoration of axonal trafficking and protection of synaptic integrity and func- tion. Neuroprotection using these strategy was confirmed in multiple mouse models of Alzheimer's Disease (AD), chronologically aged mice, in wild type mice fed with a high fat diet, and in human neurons and fibro- blasts from patients with AD and mitochondria disease. In mouse neurons expressing truncated and full-length mutant Huntingtin (mHtt) protein, treatment with partial complex I inhibitors significantly reduced mHtt aggrega- tion, restored altered cholesterol homeostasis and endocytosis. In R6/2mice, this treatment extended the sur- vival, and reduced clasping phenotype and incidents of seizures. Our ultimate goal is to develop a disease- modifying treatment for HD. Objectives of this proposal are to establish proof of concept that application of par- tial complex I inhibitors provides neuroprotection in human and mouse models of HD, and to gain the insight in critical molecular mechanisms of neuroprotection. Based on our preliminary data and the fact that mitochondri- al dysfunction and increased oxidative stress contribute to HD mechanism, we propose to test a hypothesis that application of partial complex I inhibitors could delay the onset and development of HD and protect against neuronal loss by improving mitochondrial dynamics and function and increasing the resistance to oxidative stress. The specific experimental goals are: 1) to investigate whether chronic administration of mitochondrial partial complex I inhibitor delays the onset and development of HD in bacterial artificial chromosome HD (BACHD) transgenic mice; (2) to determine the best window of therapeutic opportunity in male and female BACHD mice; (3) to establish the hierarchy of molecular mechanisms involved in neuroprotection at different stages of the disease; (4) to demonstrate the translational potential of this approach using human HD cells. The proposed studies are based on strong premise and will provide rigorous test of the hypothesis using inno- vative cell biology, biochemistry, systems biology and imaging techniques, and pharmacological and genetic interventions. The outcomes will provide the critical biological evidence to establish the rationale and the pre- clinical criteria, to support further clinical development of specific mitochondrial complex I inhibitors for HD treatment. Since the development of proprietary partial complex I inhibitors as a first in class disease modifying strategy for neurodegenerative diseases is currently in advanced stage of lead optimization in our laboratory, the outcomes of this proposal could justify the application of this new strategy for HD significantly shortening the time from the discovery to the clinical application in humans.